Exogenous retroviruses were analyzed for their influences on T cell repertoire. A defective murine leukemia virus which causes a mouse acquired immune deficiency syndrome (MAIDS) induced superantigen-like T cell activation in vitro. In vivo, this virus selectively activated and expanded CD4+ T cells expressing V-beta5, followed later in the course of infection by widespread immune deficiency in all T cells. The effect of milk-borne MMTV on the T cell receptor (TCR) repertoire was analyzed. A previously uncharacterized tumorigenic milk-borne virus in BALB/c mice (the BALB/cV virus) was found to induce deletion of T cells expressing TCR V-beta2 in developing mice. This effect was MHC-dependent. The role of MHC class II molecules in susceptibility to MMTV infection was tested for the C3H MMTV. This milk-borne virus induced V-beta14 deletion only in strains of mice bearing natural or transgenic I-E class II major histocompatibility complex (MHC) product. Moreover, susceptibility to milk-borne virus as determined by as says of viral pp28 or LTR mRNA was also dependent upon I-E expression. These findings indicate that viral infection is dependent upon superantigenic stimulation of host lymphoid cells. Although V-beta-specific superantigenic effects are a useful model for the study of TCR selection, selection may more commonly be on the basis of receptor specificity determined by multiple TCR alpha and beta chain components. Analysis of the expression of specific TCR V-alpha/V-beta pairs has indicated that V-alpha/V-beta pairing is non-random and that strain-specific differences exist in patterns of V-alpha/V-beta expression, providing a new approach to the study of repertoire selection. T cell responses to endogenous superantigen were also shown to be influenced by V-alpha as well as V-beta TCR expression.